Utilizing sinapic acid as an inhibitory antiviral agent against MERS-CoV PLpro.

Concerns about the social and economic collapse, high mortality rates, and stress on the healthcare system are developing due to the coronavirus onslaught in the form of various species and their variants. In the recent past, infections brought on by coronaviruses severe acute respiratory syndrome coronaviruses (SARS-CoV and SARS-CoV-2) as well as middle east respiratory syndrome coronavirus (MERS-CoV) have been reported. There is a severe lack of medications to treat various coronavirus types including MERS-CoV which is hazard to public health due to its ability for pandemic spread by human-to-human transmission. Here, we utilized sinapic acid (SA) against papain-like protease (PLpro), a crucial enzyme involved in MERS-CoV replication, because phytomedicine derived from nature has less well-known negative effects. The thermal shift assay (TSA) was used in the current study to determine whether the drug interact with the recombinant MERS-CoV PLpro. Also, inhibition assay was conducted as the hydrolysis of fluorogenic peptide from the Z-RLRGG-AMC-peptide bond in the presence of SA to determine the level of inhibition of the MERS-CoV PLpro. To study the structural binding efficiency Autodock Vina was used to dock SA to the MERS-CoV PLpro and results were analyzed using PyMOL and Maestro Schrödinger programs. Our results show a convincing interaction between SA and the MERS protease, as SA reduced MERS-CoV PLpro in a dose-dependent way IC50 values of 68.58 µM (of SA). The TSA showed SA raised temperature of melting to 54.61 °C near IC50 and at approximately 2X IC50 concentration (111.5 µM) the Tm for SA + MERS-CoV PLpro was 59.72 °C. SA was docked to MERS-CoV PLpro to identify the binding site. SA bound to the blocking loop (BL2) region of MERS-CoV PLpro interacts with F268, E272, V275, and P249 residues of MERS-CoV PLpro. The effectiveness of protease inhibitors against MERS-CoV has been established and SA is already known for broad range biological activity including antiviral properties; it can be a suitable candidate for anti-MERS-CoV treatment.

Herb-drug interaction: Effect of sinapic acid on the pharmacokinetics of dasatinib in rats.

Dasatinib (DAS) is a narrow therapeutic index drug and novel oral multitarget inhibitor of tyrosine kinase and approved for the first-line therapy for chronic myelogenous leukemia (CML) and Philadelphia chromosome (Ph + ) acute lymphoblastic leukemia (ALL). DAS, a known potent substrate of cytochrome (CYP) 3A, P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) and is subject to auto-induction. The dietary supplementation of sinapic acid (SA) or concomitant use of SA containing herbs/foods may alter the pharmacokinetics as well as pharmacodynamics of DAS, that may probably lead to potential interactions. Protein expression in rat hepatic and intestinal tissues, as well as the in vivo pharmacokinetics of DAS and the roles of CYP3 A2 and drug transporters Pgp-MDR1 and BCPR/ABCG2, suggested a likely interaction mechanism. The single dose of DAS (25 mg/kg) was given orally to rats with or without SA pretreatment (20 mg/kg p.o. per day for 7 days, n = 6). The plasma concentration of DAS was estimated by using Ultra-High-Performance Liquid Chromatography Mass spectrometry (UHPLC-MS/MS). The in vivo pharmacokinetics and protein expression study demonstrate that SA pretreatment has potential to alter the DAS pharmacokinetics. The increase in Cmax, AUC and AUMC proposes increase in bioavailability and rate of absorption via modulation of CYP3 A2, PgP-MDR1 and BCPR/ABCG2 protein expression. Thus, the concomitant use of SA alone or with DAS may cause serious life-threatening drug interactions.

Effects of Apigenin on Pharmacokinetics of Dasatinib and Probable Interaction Mechanism.

Dasatinib (DAS), a narrow-therapeutic index drug, Bcr-Abl, and Src family kinases multitarget inhibitor have been approved for chronic myelogenous leukemia (CML) and Ph-positive acute lymphocytic leukemia (Ph+ ALL). Apigenin (APG) has a long history of human usage in food, herbs, health supplements, and traditional medicine, and it poses low risk of damage. The concomitant use of APG containing herbs/foods and traditional medicine may alter the pharmacokinetics of DAS, that probably lead to possible herb-drug interactions. The pharmacokinetic interaction of APG pretreatment with DAS in rat plasma following single and co-oral dosing was successfully deliberated using the UPLC-MS/MS method. The in vivo pharmacokinetics and protein expression of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 demonstrate that APG pretreatment has potential to drastically changed the DAS pharmacokinetics where escalation in the Cmax, AUC(0-t), AUMC(0-inf_obs), T1/2, Tmax, and MRT and reduction in Kel, Vd, and Cl significantly in rats pretreated with APG 40 mg/kg, thus escalating systemic bioavailability and increasing the rate of absorption via modulation of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 protein expression. Therefore, the concomitant consumption of APG containing food or traditional herb with DAS may cause serious life-threatening drug interactions and more systematic clinical study on herb-drug interactions is required, as well as adequate regulation in herbal safety and efficacy.

Antioxidant, Antibacterial, and Anticancer Activity of Ultrasonic Nanoemulsion of Cinnamomum Cassia L. Essential Oil.

Cinnamomum cassia (C. assia) has long been used in traditional holistic medicine for its medicinal properties. It is used as an antioxidant, antibacterial, anti-inflammatory and anticancer agent. Cinnamon, in particular, the essential oil of C. cassia, has significant biological properties. Despite this, the volatility, stability, and insolubility of C. cassia essential oil (CEO) remain the main disadvantages that limit its application, ultimately affecting its pharmacological efficacy. To find a solution to this problem, we developed the CEO nanoemulsion (CEO-NE). For lipophilic compounds, insoluble nanoemulsion-based formulations are a popular delivery strategy. In this research work, a highly stable dosage form named CEO-NE was successfully developed using polysorbate 80 and water. The findings show that the synthesized CEO has a uniform shape with a PDI of 0.380 and an adequate particle size of 221.8 nm. The antioxidant outcomes show excellent results for CEO-NE compared to CEO against DPPH and hydrogen peroxide. The obtained antibacterial activity of CEO-NE was more efficient than that of CEO against Klebsiella pneumonia (MTCC 8911) with 0.025% and 0.05%, respectively. The CEO-NE preparation was tested against an alveolar lung adenocarcinoma cell line (A549) with an IC50 of 50.21 µg/mL for CEO and 18.05 µg/mL for CEO-NE, respectively. These results are encouraging for future translational studies on CEO-NE use in lung cancer therapy due to its excellent antioxidant, antibacterial, and killing kinetic properties.

Herbal Fennel Essential Oil Nanogel: Formulation, Characterization and Antibacterial Activity against Staphylococcus aureus.

Antimicrobial resistance (AMR) is one of the greatest threats to humanity in the world. Antibiotic-resistant bacteria spread easily in communities and hospitals. Staphylococcus aureus (S. aureus) is a serious human infectious agent with threatening broad-spectrum resistance to many commonly used antibiotics. To prevent the spread of pathogenic microorganisms, alternative strategies based on nature have been developed. Essential oils (EOs) are derived from numerous plant parts and have been described as antibacterial agents against S. aureus. Fennel essential oils were selected as antibacterial agents encapsulated in nanoparticles of polylactic acid and glycolic acid (PLGA). The optimum size of the formulation after loading with the active ingredient was 123.19 ± 6.1595 nm with a zeta potential of 0.051 ± 0.002 (23 ± 1.15 mV). The results of the encapsulation efficiency analysis showed high encapsulation of EOs, i.e., 66.4 ± 3.127. To obtain promising carrier materials for the delivery of fennel EOs, they were incorporated in the form of nanogels. The newly developed fennel oils in PLGANPs nanogels have good drug release and MIC against S. aureus. These results indicate the potential of this novel delivery system for antimicrobial therapy.

An In Silico Investigation to Explore Anti-Cancer Potential of Foeniculum vulgare Mill. Phytoconstituents for the Management of Human Breast Cancer.

Breast cancer is one of the most prevalent cancers in the world. Traditionally, medicinal plants have been used to cure various types of diseases and disorders. Based on a literature survey, the current study was undertaken to explore the anticancer potential of Foeniculum vulgare Mill. phytoconstituents against breast cancer target protein (PDB ID: 6CHZ) by the molecular docking technique. Molecular docking was done using Autodock/vina software. Toxicity was predicted by the Protox II server and drug likeness was predicted by Molinspiration. 100 ns MD simulation of the best protein-ligand complexes were done using the Amber 18 tool. The present molecular docking investigation has revealed that among the 40 selected phytoconstituents of F. vulgare, α-pinene and D-limonene showed best binding energy (-6 and -5.9 kcal/mol respectively) with the breast cancer target. α-Pinene and D-limonene followed all the parameters of toxicity, and 100 ns MD simulations of α-pinene and D-limonene complexes with 6CHZ were found to be stable. α-Pinene and D-limonene can be used as new therapeutic agents to cure breast cancer.

Clopidogrel-herb Interactions: A Pharmacokinetic and Pharmacodynamic Assessment in a Rat Model.

BACKGROUND: Herbs usually contain a mixture of biologically active constituents, which can interact with numerous prescribed drugs and alter their safety profiles. OBJECTIVES: The current investigation was aimed to evaluate the effect of commonly used herbal products including black seed (Nigella sativa), garden cress (Lepidium sativum), and fenugreek (Trigonella foenum-graecum) on the pharmacokinetics and pharmacodynamics of clopidogrel using a Wistar rat model. METHODS: A GC-MS analysis revealed the presence of several phytoconstitutents (polyphenols) in the extracts of black seed, garden cress, and fenugreek. These polyphenols have the potential to interfere with clopidogrel effect. Plasma concentrations of clopidogrel were measured at different time points in the absence and presence of the concurrent use of tested herbal products and the pharmacokinetic parameters were calculated. Bleeding time was measured in various groups as a measure of the antiplatelet effect of clopidogrel. RESULTS: Area under the plasma concentration-time curves (AUC0-∞) of clopidogrel were 35.53 ±0.89 µg/ml*h (p<0.05), 26.01 ±0.90 µg/ml*h (p>0.05) and 32.80 ±2.51 µg/ml*h (p<0.05) in the black seed, garden cress and fenugreek group, respectively, compared with that of the control group (27.02 ±0.42 µg/ml*h). Treatment with black seed also caused an increase in clopidogrel Cmax by 31.52% (p<0.05) and with fenugreek by 21.42% (p<0.05); Cmax, did not changed with garden cress treatment (6.48 ±0.15 µg/ml versus 6.12 ±0.21 µg/ml, p>0.05). The pharmacodynamic evaluation of the antiplatelet effect of clopidogrel in the presence of herbal products treatment showed a significant prolongation in the bleeding time from a control baseline by ~22-26%, and by added ~8-12% in reference to clopidogrel therapeutic effect (p<0.05). CONCLUSION: The concurrent use of black seed, fenugreek, or garden cress can alter the pharmacokinetics and pharmacodynamics of clopidogrel to varying degrees due to the presence of various bioactive polyphenols. This is probably due to changes in drug disposition and its antiplatelet action. Further confirmation can determine the clinical relevance of these observations and identify the exact constituents responsible for such activities.

Effects of garden cress, fenugreek and black seed on the pharmacodynamics of metoprolol: an herb-drug interaction study in rats with hypertension.

CONTEXT: Garden cress (GC), fenugreek (FG), and black seed (BS) are traditional herbal medicine for managing hypertension. OBJECTIVE: The effects of the three herbs on the pharmacodynamics of metoprolol tartrate (MT) in hypertensive rats were investigated. MATERIALS AND METHODS: Wistar rats were divided in five groups (n = 6). Group I served as normal control group and Group II (hypertensive control group) had rats treated orally with N-nitro L-arginine methyl ester (L-NAME, 40 mg/kg/day) only. Groups III, IV, and V rats were orally treated with L-NAME (40 mg/kg/day) + GC (300 mg/kg, once daily), L-NAME (40 mg/kg/day) + FG (300 mg/kg, once daily) and L-NAME (40 mg/kg/day) + BS (300 mg/kg, once daily), respectively, for 2 weeks, and on the 14th day, blood pressure and heart rate were recorded using a tail-cuff blood pressure-measuring system. On the 16th day, a single dose of MT (10 mg/kg) was orally administered, and the rats' blood pressure and heart rate were recorded. RESULTS: GC, FG, and BS decreased systolic blood pressure (SBP) by 8.7%, 8.5%, and 8.7%, respectively, in hypertensive rats. A greater decrease in SBP by 14.5%, 14.8%, and 16.1% was observed when hypertensive rats were treated with L-NAME + GC + MT, L-NAME + FG + MT, and L-NAME + BS + MT, respectively. Similarly, hypertensive rats treated with the combination of herbs and MT had significantly lower diastolic blood pressure (DBP) than those treated with herbs alone and those treated with L-NAME alone. CONCLUSIONS: The combination of investigated herbs and MT had a beneficial effect on hypertension. However, the concurrent administration of drugs, particularly those predominantly cleared through CYP450 2D6-catalyzed metabolism, with the three investigated herbs should be considered with caution.

Effect of Hibiscus sabdariffa and Zingiber officinale on pharmacokinetics and pharmacodynamics of amlodipine.

OBJECTIVES: To study the effect of Zingiber officinale and Hibiscus sabdariffa on pharmacokinetics and pharmacodynamics of amlodipine. METHODS: Hypertension was induced in rats (SBP 173.2 ± 1.7 mmHg, mean, 1-24 h). Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP) and heart rate (HR) of group-I (amlodipine treated), group-II (Z. officinale, and Z. officinale + amlodipine) and group-III (H. sabdariffa, and H. sabdariffa + amlodipine) animals were measured by "tail-cuff system". Pharmacokinetics of amlodipine with and without herbs (Z. officinale or H. sabdariffa) was also investigated. RESULTS: Z. officinale as well as H. sabdariffa decreased the SBP, DBP and MBP. Concurrent treatment with Z. officinale + amlodipine (SBP 129.4 ± 4.5) or H. sabdariffa + amlodipine (SBP 130.4 ± 3.9) showed higher decrease in BP (mean, 1-24h), than individually administered amlodipine (SBP 149.5 ± 2.4) or Z. officinale (SBP 150.2 ± 3.1) or H. sabdariffa (SBP 139.1 ± 1.2). These herbs also influenced the Cmax, AUC0-t, and Tmax of amlodipine. H. sabdariffa increased AUC0-t of amlodipine from 81.8 ± 14.7 to 125.0 ± 10.6 (ng h/mL). CONCLUSION: Simultaneous administration of Z. officinale or H. sabdariffa with amlodipine, improves its pharmacodynamic response.

Effect of Nigella sativa and Fenugreek on the Pharmacokinetics and Pharmacodynamics of Amlodipine in Hypertensive Rats.

BACKGROUND: The present article is related to in-vitro and in-vivo herb-drug interaction studies. OBJECTIVES: This study aimed to investigate the effect of Nigella sativa and fenugreek on the pharmacodynamics and pharmacokinetics of amlodipine. METHOD: Hypertensive rats of group-I were treated with amlodipine and rats of group-II and III were treated with N. sativa, and N. sativa + amlodipine and fenugreek, and fenugreek + amlodipine, respectively. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP) of group-I, II and III rats were measured by the "tail-cuff system". RESULTS: N. sativa, as well as fenugreek, reduced the SBP, DBP and MBP. Simultaneously, administration of fenugreek + amlodipine or N. sativa + amlodipine showed better control of BP. Individually, fenugreek, as well as N. sativa, showed a surprising reduction in the heart rate. There was no remarkable effect of any of these two herbs on Cmax, AUC0-t, Kel, and terminal elimination half-life of amlodipine, but fenugreek altered the Tmax of amlodipine significantly, from 2 ± 1.2h in control to 7.2 ± 1.7h in fenugreek treated group, probably by delaying the absorption. CONCLUSION: Results of pharmacodynamics and pharmacokinetics studies suggested that simultaneous administration of fenugreek or N. sativa with amlodipine improved the pharmacological response of amlodipine in hypertensive rats, though there was no remarkable change in pharmacokinetic parameters (Cmax, Kel, elimination t1/2, and AUC0-t).

Effect of Hibiscus sabdariffa and Zingiber officinale on the antihypertensive activity and pharmacokinetic of losartan in hypertensive rats.

The present study aimed to determine the effect of Hibiscus sabdariffa and Zingiber officinale on antihypertensive activity and pharmacokinetic of losartan in hypertensive rats.Hypertension was induced in rats by oral administration of L-NAME (40 mg/kg per day). Pharmacodynamics and pharmacokinetics of losartan were evaluated without and with herbal treatment in hypertensive rats.Treatment of hypertensive rats with investigated herbs substantially reduced systolic blood pressure (SBP), and diastolic blood pressure (DBP) of rats. Treatment of rats (n = 5) with L-NAME plus H. sabdariffa plus losartan and L-NAME plus Z. officinale plus losartan reduced SBP by 16.20% and 14.88% and DBP by 14.82% and 17.52% respectively after 12 h, as compared to L-NAME alone treated rats. In a pharmacokinetic study, the Cmax and AUC0-t of losartan in L-NAME plus H. sabdariffa plus losartan and L-NAME plus Z. officinale plus losartan treated rats was increased by 0.7, 1.99 and 1.51, 3.00 fold respectively in comparison to the Cmax and AUC0-t obtained for L-NAME plus losartan treated group. In conclusion, both the investigated herbs significantly increased the antihypertensive effect and plasma concentration of losartan in L-NAME induced hypertensive rats. The current study predicted that the herb-drug interaction between H. sabdariffa-losartan and Z. officinale-losartan could occur; hence these results in rats may warrant further studies in humans, either in humans or in in vitro human liver microsomes.

Thymoquinone treatment modulates the Nrf2/HO-1 signaling pathway and abrogates the inflammatory response in an animal model of lung fibrosis.

The present study investigates the therapeutic potential of thymoquinone (TQ) in bleomycin-induced lung fibrosis (BMILF) and elucidates the target-signaling pathway for its effect. Lung fibrosis was induced in rats by a single intra-tracheal instillation of bleomycin (BM) (6.5 U/kg) followed by thymoquinone treatment (10 and 20 mg/kg p.o.) for 28 days. Control rats received saline instead of TQ. Changes in body weight, inflammatory cells count, cytokines levels, and biochemical parameters of the broncho-alveolar lavage fluid (BALF) were recorded. In addition, a histopathology examination and western blotting were performed on lung tissues. BM administration resulted in a significant weight loss, which was ameliorated by TQ treatment. BMILF was associated with a reduction in the antioxidant mechanisms and increased lipid peroxidation. Furthermore, elevated levels of inflammatory cytokines, MMP-7 expression, apoptotic markers (caspase 3, Bax, and Bcl-2), and fibrotic changes including TGF-ß and hydroxyproline levels in lung tissues were evident. These abnormalities were diminished with TQ treatment. Likewise, altered total and differential cell count in BALF was significantly improved in rats treated with TQ. TQ also produced a dose-dependent reduction in the expressions of Nrf2, Ho-1 and TGF-ß. These results propose that the Nrf2/Ho-1 signaling pathway is a principal target for TQ protective effect against BMILF in rats. Furthermore, TQ decreases inflammatory oxidative stress possibly through the modulation of nuclear factor Kappa-B (NF-κB) and thereby minimization of collagen deposition in the lung. Therefore, TQ can be developed as a potential therapeutic modularity in BMILF for human use.

Cisplatin bioconjugated enzymatic GNPs amplify the effect of cisplatin with acquiescence.

Enzymatic gold nanoparticles (B-GNPs) have been synthesized using a natural anticancer agent bromelain (a cysteine protease) and these nanoparticles were used to bioconjugate Cisplatin (highly effective against osteosarcoma and lung cancer). Cisplatin bioconjugated bromelain encapsulated gold nanoparticles (B-C-GNPs) were found profoundly potent against same cancers at much lower concentration with minimum side effects due to the synergistic effect of bromelain. The B-C-GNPs have been observed to inhibit the proliferation of osteosarcoma cell lines Saos-2 and MG-63 with IC50 estimation of 4.51 µg/ml and 3.21 µg/ml, respectively, and against small lung cancer cell line A-549 with IC50 2.5 µg/ml which is lower than IC50 of cisplatin against same cell lines. The B-GNPs/B-C-GNPs were characterized by TEM, UV-Visible spectroscopy, Zeta potential and DLS to confirm the production, purity, crystalline nature, stability of nanoemulsion, size and shape distribution. The change in 2D and 3D conformation of bromelain after encapsulation was studied by Circular Dichroism and Fluorometry, respectively. It was found that after encapsulation, a 19.4% loss in secondary structure was observed, but tertiary structure was not altered significantly and this loss improved the anticancer activity. The confirmation of bioconjugation of cisplatin with B-GNPs was done by UV-Visible spectroscopy, TEM, FTIR, 2D 1H NMR DOSY and ICP-MS. Further, it was found that almost ~4 cisplatin molecules bound with each B-GNPs nanoparticle.

Beetroot juice alleviates isoproterenol-induced myocardial damage by reducing oxidative stress, inflammation, and apoptosis in rats.

Beetroot (Beta vulgaris L.) juice (BRJ) is a good source of betalain (betacyanins and betaxanthin) pigments and exhibits antioxidant, anti-inflammatory, and chemo-preventive activities in vitro and in vivo. The current study was performed to determine the cardioprotective effect of BRJ on lipid peroxidation, antioxidant defense, functional impairment, and histopathology in rats with isoproterenol (ISP)-induced myocardial injury. Myocardial ischemia was induced by ISP (85 mg/kg) s.c. injection at 24 h intervals, followed by oral administration of BRJ for 28 days at doses of 150 and 300 mg/kg. ISP-induced myocardial damage was confirmed by an increase in heart weight to body weight ratio, % infarction size, serum cardiac indices (AST, ALT, GGT, ALP, LDH and CK-MB), and histological alterations in the myocardium. Pretreatment with BRJ (150 and 300 mg/kg) followed by ISP induction reduced oxidative/nitrosative stress and restored the cardiac endogenous antioxidants in rats. ISP augmented cardiac inflammatory cytokines (TNF-α, IL-6 and IL-10), myeloperoxidase activity, NF-κB DNA binding and protein expression of NF-κB (p65), and the hyperlipidemia level was significantly reduced by the BRJ pretreatment. Furthermore, the BRJ pretreatment significantly reduced caspase-3, Bax, and MMP-9 protein expression, enhanced the Bcl-2 antiapoptotic protein expression, alleviated the extent of histological damage, myonecrosis, and edema, and maintained the architecture of cardiomyocytes. These findings suggest that BRJ pretreatment mitigates cardiac dysfunction and structural damages by decreasing oxidative stress, inflammation, and apoptosis in cardiac tissues. These results further support the use of BRJ in traditional medicine against cardiovascular diseases.

Effects of sinapic acid on hepatic cytochrome P450 3A2, 2C11, and intestinal P-glycoprotein on the pharmacokinetics of oral carbamazepine in rats: Potential food/herb-drug interaction.

Dietary supplements, herbal medicines, and other foods may affect the pharmacokinetics and/or pharmacodynamics of carbamazepine (CBZ), which may possibly lead to potential drug-drug/herb-drug interactions, as CBZ has a narrow therapeutic window. Sinapic acid (SA) is a bioactive phytoconstituent used as a dietary supplement for the treatment of epilepsy. This study determined the effects of SA on the pharmacokinetics of CBZ and proposed a possible interaction mechanism in twenty-four male wistar rats (180-210 g). A single CBZ dose (80 mg/kg) was administered orally to rats with or without SA pretreatment (20 mg/kg p.o. per day for 7 days, n = 6). The CBZ concentration in plasma samples was determined by using a sensitive reversed-phase high-performance liquid chromatography assay. The pharmacokinetic parameters were calculated by using non-compartmental analysis. Significance was determined through Dunnett's multiple comparison test or one-way analysis of variance as appropriate; p < 0.05 were considered significant. The change in the pharmacokinetic parameters (Cmax, Tmax, AUC0-t, AUC0-∞, T½, and kel) of CBZ was evaluated after the administration of CBZ alone or after CBZ co-administration with SA pretreatment. The plasma concentration of CBZ was higher after SA pretreatment than that without pretreatment. The pharmacokinetics of orally administered CBZ were found to be significantly altered (p < 0.05) in rats pretreated with SA compared to those in rats administered CBZ alone. The increases in the Cmax, AUC0-t, T1/2, and MRT of CBZ were 29.79%, 57.18%, 77.18%, and 58.31%, respectively, whereas the kel and apparent oral CL/F were significantly reduced (p < 0.05) in rats pretreated with SA compared to those in rats not pretreated with SA (43.87% and 42.50%, respectively). However, no significant change was observed in the Tmax of CBZ in rats pretreated with SA compared to that in rats that did not receive pretreatment. The enhancement in Cmax, AUC0-t, T1/2, and MRT and the reduction in Kel and CL/F values resulted from the significant inhibition of CYP3 A2, the CYP2C11-mediated metabolism of CBZ in the liver, and the inhibition of intestinal P-glycoprotein/MDR1, which enhanced the rate of CBZ absorption. Further studies are required to determine the clinical relevance of these observations.

Variability in Catechin and Rutin Contents and Their Antioxidant Potential in Diverse Apple Genotypes.

Catechins and rutin are among the main metabolites found in apple fruit. Sixty apple genotypes, harvested in 2016 and 2017, were analyzed for their phenolic content and antioxidant activity. The HPLC analysis showed that the catechin concentration ranged from 109.98 to 5290.47 µg/g, and the rutin concentration ranged from 12.136 to 483.89 µg/g of apple fruit. The level of DPPH activity ranged from 9.04% to 77.57%, and almost half of the 15 genotypes showed below 30⁻40% DPPH activity. The apple genotypes 'Lal Ambri', 'Green Sleeves', and 'Mallus floribunda' showed the highest DPPH activity of between 70% and 80%, while 'Schlomit', 'Luxtons Fortune', 'Mayaan', 'Ananas Retrine', and 'Chaubatia ambrose' showed the lowest ferric reducing antioxidant power (FRAP) activity (0.02⁻0.09%). Statistical analysis showed a correlation between DPPH activity and catechin content (r = 0.7348) and rutin content (r = 0.1442). Regarding antioxidant activity, fractionated samples of apple genotypes revealed significant activity comparable to that of ascorbic acid. There was also a consistent trend for FRAP activity among all apple genotypes and a significant positive correlation between FRAP activity and rutin content (r = 0.244). Thus, this study reveals a significant variation in antioxidant potential among apple genotypes. This data could be useful for the development of new apple varieties with added phytochemicals by conventional and modern breeders.

Biogenic pentagonal silver nanoparticles for safer and more effective antibacterial therapeutics.

BACKGROUND: Biological synthesis of nanomaterials possesses unprecedented potential in the production of nanomaterials due to their ability to produce nanomaterials with improved biocompatibility in addition to eco-friendly synthetic procedures. METHODS: This article reports the isolation of an air-borne fungus from the campus of Integral University, Lucknow, with an exceptional ability to withstand very high concentrations of silver salt. The fungus was found to produce pentagonal silver nanoparticles (AgPgNps) when silver ions were reduced from silver nitrate. Molecular analysis and biochemical characterization techniques based on 18-seconds rRNA identified the fungus to belong to the Aspergillus sp. with the NCBI accession no KF913249. Material characterization techniques including ultraviolet (UV)-visible spectroscopy, transmission electron microscopy, and zeta potential analysis were used to satisfactorily characterize the as-synthesized AgPgNps. RESULTS: The AgPgNps synthesized by the fungus Aspergillus sp. exhibit an absorption that is maximum centered at about 416 nm, with a standard particle size of 23.22±2 nm. These AgPgNps exhibited broad-spectrum antimicrobial activities against an array of bacterial pathogens with remarkable minimum inhibitory concentration (MIC50) values: Staphylococcus aureus (ATCC 25923) - 9.230 µg/mL, Bacillus sp. (ATCC 14593) - 12.781 µg/mL, Escherichia coli (ATCC 25922) - 5.063 µg/mL, and Klebsiella pneumoniae (ATCC 13883) - 5.426 µg/mL. In vitro cytotoxicity analysis of biosynthesized AgPgNps showed a dose-response activity against human cervical cancer cell line (HeLa) and adenocarcinoma cells (A549) with MIC50 values of 0.038 µg/mL and 0.044 µg/mL, respectively. CONCLUSION: These findings are very crucial to evaluate the biosynthetic process for the synthesis of nanoparticles (NPs) with unique properties. These NPs may find potential applications in sensing, medicine, and antimicrobial and anticancer therapies.

Antioxidant and Antimutagenic Activities of Different Fractions from the Leaves of Rhododendron arboreum Sm. and Their GC-MS Profiling.

In this era of urbanization and environmental pollution, antioxidants and antimutagens derived from plants are promising safeguards for human health. In the current investigation, we analyzed the antioxidant and antimutagenic effects of the hexane, chloroform, and ethyl acetate fractions of Rhododendron arboreum Sm. leaves and determined their chemical composition. The different fractions inhibited lipid peroxidation, repressed the production of nitric oxide radicals, and prevented deoxyribose degradation. The antimutagenic activity of the leaf fractions was analyzed against 4-nitro-O-phenylenediamine, sodium azide and 2-aminofluorene mutagens in two test strains (TA-98 and TA-100) of Salmonella typhimurium. The experiment was conducted using pre- and co-incubation modes. The best results were obtained in the pre-incubation mode, and against indirect acting mutagen. The presence of a number of bioactive constituents was confirmed in the different fractions by GC-MS analysis. The study reveals the strong antioxidant and antimutagenic activity of R. arboreum leaves. We propose that those activities of R. arboreum might correspond to the combined effect of the phytochemicals identified by GC-MS analysis. To the best of our knowledge, this is the first report on the antimutagenic activity of R. arboreum leaves.

Indole Derivatives as Cyclooxygenase Inhibitors: Synthesis, Biological Evaluation and Docking Studies.

A new series of 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N'-[(E)-(substituted phenyl) methylidene] acetohydrazide derivatives (S1⁻S18) were synthesized and evaluated for their anti-inflammatory activity, analgesic activity, ulcerogenic activity, lipid peroxidation, ulcer index and cyclooxygenase expression activities. All the synthesized compounds were in good agreement with spectral and elemental analysis. Three synthesized compounds (S3, S7 and S14) have shown significant anti-inflammatory activity as compared to the reference drug indomethacin. Compound S3 was further tested for ulcerogenic index and cyclooxygenase (COX) expression activity. It was selectively inhibiting COX-2 expression and providing the gastric sparing activity. Docking studies have revealed the potential of these compounds to bind with COX-2 enzyme. Compound S3 formed a hydrogen bond between OH of Tyr 355 and NH2 of Arg 120 with carbonyl group and this hydrogen bond was similar to that formed by indomethacin. This study provides insight for compound S3, as a new lead compound as anti-inflammatory agent and selective COX-2 inhibitor.

Nepeta deflersiana attenuates isoproterenol-induced myocardial injuries in rats: Possible involvement of oxidative stress, apoptosis, inflammation through nuclear factor (NF)-κB downregulation.

BACKGROUND: Nepeta deflersiana (Lamiaceae) is a perennial herb used in the Saudi and Yemeni folk medicine as an anti-inflammatory, carminative, and antirheumatic agent. PURPOSE: This study explores the phytochemistry of the plant and the cardioprotective effect of N. deflersiana ethanolic extract (NDEE) against isoproterenol (ISP)-induced myocardial injury in rats. DESIGN/METHODS: Cardiac function, serum cardiac enzymes, myocardial antioxidants, inflammatory, and apoptotic biomarkers, and histopathological parameters were studied in ISP-injured Wistar rat heart tissues. RESULTS: To the best of our knowledge, this is the first study to report the isolation of nine secondary metabolites from this plant: 1α-hydroxy-7α,14α,18-triacetoxy-isopimara-8,15-diene (1), ß-sitosterol (2), lupeol (3), ursolic acid (4), 2,3-dihydroxy ursolic acid (5), caffeic acid (6), methyl rosmarinate (7), rosmarinic acid (8), and an irridoid glucoside 8-epi-7-deoxyloganic acid (9). To explain the mechanisms underlying the cardioprotective effect of NDEE, we evaluated the redox-sensitivity of NDEE in ISP-induced cardiac injury. The oral administration of NDEE (50 and 100 mg/kg b.w) prevented the depletion of endogenous antioxidants (CAT, SOD, NP-SH, and NO) and myocyte injury marker enzymes and inhibited lipid peroxidation (MDA, MPO). Moreover, NDEE downregulated the expression of pro-inflammatory cytokines (TNFα, IL-6, and IL-10) and apoptotic markers (caspase-3 and Bax) and upregulated the anti-apoptotic protein Bcl2. Furthermore, NDEE pretreatment significantly downregulated cardiac NF-κB (p65) expression, NF-κB-DNA binding activity, and MPO activity. Histological data showed that NDEE pretreatment reduced myonecrosis, edema, and infiltration of inflammatory cells and restored the architecture of cardiomyocytes. CONCLUSION: NDEE demonstrated strong antioxidant, cardioprotective, anti-inflammatory, and anti-apoptotic potential against myocardial damage. This further endorses the use of N. deflersiana in Yemeni folk medicine against cardiovascular diseases.